Table S1. ARIC study visit 2 participant characteristics by sex-specific tertiles of the CMI. ... 2 Table S2. Comparison of sex-specific tertiles of CMI with other muscle mass indices based on serum creatinine and serum cystatin C at ARIC visit 5 (A) and visit 2 (B). ... 4 Table S3. AUCs for frailty models and C-statistics for mortality models with related measures in men and women. . 5 Figure S1. Adjusted odds ratios of frail (vs robust) with continuous CMI in men and women at visits 5 in ARIC. ... 7 References ... 8

(2)

Table S1. ARIC study visit 2 participant characteristics by sex-specific tertiles of the CMI.

Overall Men, N=5616 Women, N=7170

CMI tertile CMI tertile

1 2 3

p for trend

1 2 3 p for

trend

N=1872 N=1872 N=1872 N=2390 N=2390 N=2390

CMI,

mg/day/1.73m²

996.6 (258.2)

330.9 - 1041.1

1041.2 - 1257.9

1258.3 - 2313.3

234.3 - 786.5

786.5 - 944.2

944.3 - 1910.3

Age, years 57.4

(5.7)

59.9 (5.6)

57.8 (5.6)

55.6

(5.3) <0.001 59 (5.5) 57.3 (5.6)

55.0

(5.2) <0.001

Black race 24.4%

(3125)

9.6%

(180)

16.5%

(308)

34.6%

(648) <0.001

21.4%

(512)

24.9%

(594)

36.9%

(883) <0.001

Study Site <0.001 <0.001

Forsyth County, NC

25.7%

(3291)

31.7%

(594)

26.3%

(492)

21.5%

(402)

29.6%

(707)

25.8%

(617)

20%

(479) Jackson, MS 21.8%

(2783)

8.4%

(157)

14.4%

(270)

30.7%

(575)

18.7%

(447)

22.4%

(536)

33.4%

(798) Minneapolis,

MN

27.1%

(3464)

25.8%

(483)

32.4%

(606)

29.1%

(545)

21.3%

(508)

26.7%

(637)

28.7%

(685) Washington

County, MD

25.4%

(3248)

34.1%

(638)

26.9%

(504)

18.7%

(350)

30.5%

(728)

25.1%

(600)

17.9%

(428)

Education <0.001 <0.001

Less than high school

21.2%

(2701)

24.9%

(464)

20.7%

(387)

17.8%

(333)

27.2%

(649)

19.5%

(466)

16.8%

(402) High school

or vocational school

41.8%

(5334)

38.4%

(716)

35.9%

(670)

35.7%

(668)

46.6%

(1113)

47.5%

(1135)

43.2%

(1032) More than

high school

37.1%

(4731)

36.8%

(686)

43.4%

(811)

46.5%

(869)

26.2%

(624)

33%

(787)

39.9%

(954)

Weight, kg 79.4

(16.9)

86.9 (16.4)

85.6 (13.9)

85.6

(13.2) 0.005 76.9 (19)

73.7 (16.4)

71.9

(14.3) <0.001

Height, cm 168.4

(9.3)

175.8 (6.6)

176.2 (6.4)

176.6

(6.5) <0.001

161.6 (6.1)

162.2 (5.9)

163.3

(5.8) <0.001

BMI, kg/m² 28.0

(5.4)

28.2

(4.9) 27.6 (4) 27.5

(3.7) <0.001 29.5 (7) 28.1 (6) 27.0 (5)

<0.001 BSA, m² 1.9 (0.2) 2.1 (0.2) 2.0 (0.2) 2.0 (0.2) 0.186 1.8 (0.2) 1.8 (0.2) 1.8 (0.2) <0.001 Waist-to-hip ratio 0.9 (0.1) 1.0 (0.1) 1.0 (0.1) 1.0 (0.1) <0.001 0.9 (0.1) 0.9 (0.1) 0.9 (0.1) <0.001

Smoking status <0.001 <0.001

current 22.02%

(2816)

33.2%

(622)

22.8%

(426)

15.2%

(285)

28.9%

(690)

19%

(453)

14.2%

(340)

former 37.81%

(4835)

47.3%

(885)

51%

(955)

51.7%

(968)

25.7%

(614)

28.6%

(683)

30.5%

(730)

never 40.16%

(5135)

19.5%

(365)

26.2%

(491)

33.1%

(619)

45.4%

(1086)

52.5%

(1254)

55.2%

(1320)

Serum creatinine 0.8 (0.4) 0.9 (0.5) 0.9 (0.2) 1.0 (0.3) <0.001 0.6 (0.5) 0.7 (0.2) 0.8 (0.2) <0.001 Serum cystatin C 0.9 (0.3) 1.1 (0.4) 0.9 (0.1) 0.8 (0.2) <0.001 1.0 (0.5) 0.8 (0.2) 0.8 (0.1) <0.001

eGFRcys 91.4

(18.5)

78.2 (18.4)

93.2 (14.9)

103.4

(13.2) <0.001

80.3 (20.1)

92.5 (15.1)

101

(12.5) <0.001

eGFRB2M 84.9

(16.2)

76.0 (15.5)

85.3 (13.4)

91.6

(13.4) <0.001

77.5 (17.6)

86.1 (14.7)

92.3

(14.5) <0.001

ACR, mg/g Cr n/a n/a n/a n/a n/a n/a n/a n/a n/a

hs CRP, mg/L n/a n/a n/a n/a n/a n/a n/a n/a n/a

Total cholesterol,

mmol/L 5.4 (1.0) 5.2 (1.0) 5.3 (1.0) 5.3 (1.0) <0.001

5.6 (1.1) 5.6 (1.0) 5.5 (1.0) 0.015 HDL cholesterol,

mmol/L 1.3 (0.4) 1.0 (0.3) 1.1 (0.3) 1.2 (0.4) <0.001

1.3 (0.4) 1.4 (0.4) 1.5 (0.4) <0.001

(3)

Hypertension 35.5%

(4539)

39.8%

(745)

32.6%

(610)

34.3%

(643)

<0.001 44%

(1052)

32.2%

(770)

30.1%

(719)

<0.001

Diabetes 11.4%

(1461)

13.4%

(250)

10.6%

(199)

10.4%

(194)

0.004 15.6%

(372)

10%

(239)

8.7%

(207)

<0.001

CHD 5.7%

(735)

14.5%

(272)

9.2%

(173)

5.9%

(110)

<0.001 4.2%

(100)

1.5%

(37)

1.8%

(43)

<0.001

Number of

medications 2.8 (2.9) 2.5 (2.7) 1.9 (2.3) 1.8 (2.4) <0.001

3.6 (3.2) 3.2 (2.9) 3.1 (2.9) <0.001 Polypharmacy

(10 or more medications

2.2%

(279)

1.5%

(29)

0.7%

(13)

1.2%

(22)

0.281

3.7%

(89)

2.6%

(62)

2.7%

(64)

0.034

Mean (SD) or % (N) shown in the table. ACR and hs-CRP show median [IQR]. ACR and high sensitivity CRP were not available at visit 2.

P-value for trend:

Continuous variables: derived from regression of variable on ordinal variable of CMI tertile.

Categorical variables: Cochran-Armitage trend test, except site and smoking status which report p-value for chi square test of independence.

(4)

Table S2. Comparison of sex-specific tertiles of CMI with other muscle mass indices based on serum creatinine and serum cystatin C at ARIC visit 5 (A) and visit 2 (B).

A. Visit 5 Mean (sd)

Men, N=2056 Women, N=2583

CMI tertile CMI tertile

1 2 3 p for

trend

1 2 3 p for

trend

N=686 N=685 N=685 N=861 N=861 N=861

CMI, mg/day/1.73m² 714.6 (94.8)

927.5 (50.9)

1185.5

(142.5) <0.001 555.4 (67.4)

720.4 (43.2)

915

(104.9) <0.001 Estimated creatinine

excretion rate,(1) mg/day/1.73m²

1259.2 (63.8)

1265.5 (56.8)

1277.3

(52.5) <0.001 918.3 (113.4)

914.2 (104.7)

917.5

(94.6) 0.867 eGFRcys-eGFRcr(2),

ml/min/1.73 m² -22.1 (9.2) -10.9 (5.6) 4.8 (8.9) <0.001 -23.4 (9.3) -11.3 (6.3) 3.3 (8.1) <0.001 eGFRcys/eGFRcr(3) 0.7 (0.1) 0.9 (0.1) 1.1 (0.1) <0.001 0.7 (0.1) 0.8 (0.1) 1.1 (0.1) <0.001 Scr/Scys(4), mg/dl per

mg/l 0.8 (0.1) 0.9 (0.1) 1.1 (0.1) <0.001 0.6 (0.1) 0.8 (0.1) 0.9 (0.1) <0.001 Serum creatinine

alone, mg/dl 1.2 (0.5) 1.1 (0.3) 1.1 (0.3) <0.001 0.9 (0.4) 0.9 (0.3) 0.9 (0.2) <0.001 Serum cystatin C

alone, mg/l 1.5 (0.6) 1.2 (0.2) 1.0 (0.2) <0.001 1.5 (0.5) 1.2 (0.3) 1.0 (0.2) <0.001 P-value for trend derived from a linear regression of the variable of interest on an ordinal variable of tertiles of CMI. All ratios (i.e., eGFRcys/eGFRcr and Scr/ Scys) were log-transformed.

B. Visit 2 Mean (sd)

Men, N=5616 Women, N=7170

Creatinine muscle index tertile Creatinine muscle index tertile

1 2 3 p for

trend

1 2 3 p for

trend

N=1872 N=1872 N=1872 N=2390 N=2390 N=2390

CMI, mg/day/1.73m² 897.4 (111.9)

1146.1 (61.8)

1428.6

(151.4) <0.001 669.5 (91.2)

864.9 (46.3)

1077.7

(114.1) <0.001 Estimated creatinine

excretion rate,(1) mg/day/1.73m²

1345.2 (54.9)

1352.4 (47.8)

1367.7

(46) <0.001 1024.2 (101.1)

1018.3 (90.3)

1024.8

(78.3) 0.819 eGFRcys-eGFRcr(2),

ml/min/1.73 m² -19.6 (11) -3.7 (7.1) 11.9 (9.2) <0.001 -20.4

(12.2) -6.2 (7) 7.9 (8.9) <0.001 eGFRcys/eGFRcr(3) 0.8 (0.1) 1.0 (0.1) 1.1 (0.1) <0.001 0.8 (0.1) 0.9 (0.1) 1.1 (0.1) <0.001 Scr/Scys(4), mg/dl per

mg/l 0.8 (0.1) 1.0 (0.1) 1.2 (0.1) <0.001 0.6 (0.1) 0.8 (0.1) 1.0 (0.1) <0.001 Serum creatinine

alone, mg/dl 0.9 (0.5) 0.9 (0.2) 1.0 (0.3) <0.001 0.6 (0.5) 0.7 (0.2) 0.8 (0.2) <0.001 Serum cystatin C

alone, mg/l 1.1 (0.4) 0.9 (0.1) 0.8 (0.2) <0.001 1.0 (0.5) 0.8 (0.2) 0.8 (0.1) <0.001 P-value for trend derived from a linear regression of the variable of interest on an ordinal variable of tertiles of CMI. All ratios (i.e., eGFRcys/eGFRcr and Scr/ Scys) were log-transformed.

(5)

Table S3. AUCs for frailty models and C-statistics for mortality models with related measures in men and women.

AUC for frail and prefrail vs. robust models

Men Women

Visit 5: AUC for frailty AUC 95%CI,

lower

95%CI, upper

p-value AUC 95%CI, lower

95%CI, upper

p-value

Base model 0.760 0.709 0.811 0.753 0.718 0.788

Creatinine Muscle Index 0.827 0.783 0.871 0.002 0.791 0.759 0.822 0.004

eGFRcys-eGFRcr 0.785 0.737 0.832 0.039 0.776 0.744 0.808 0.029

eGFRcys/eGFRcr 0.811 0.766 0.856 0.007 0.777 0.745 0.809 0.037

Scr/Scys 0.793 0.746 0.840 0.032 0.769 0.736 0.802 0.112

Estimated creatinine excretion rate 0.770 0.720 0.821 0.129 0.752 0.717 0.787 0.917

Serum creatinine alone 0.806 0.761 0.851 0.002 0.765 0.729 0.800 0.088

Serum cystatin C alone 0.845 0.805 0.886 <0.001 0.793 0.761 0.824 <0.001

Visit 5: AUC for prefrail AUC 95%CI,

lower

95%CI, upper

AUC 95%CI,

lower

95%CI, upper

Base model 0.655 0.630 0.679 0.647 0.625 0.669

Creatinine Muscle Index 0.669 0.646 0.693 0.015 0.656 0.634 0.678 0.027

eGFRcys-eGFRcr 0.664 0.640 0.688 0.066 0.653 0.631 0.675 0.073

eGFRcys/eGFRcr 0.666 0.642 0.690 0.035 0.654 0.632 0.676 0.065

Scr/Scys 0.666 0.642 0.690 0.029 0.653 0.631 0.675 0.066

Serum creatinine alone 0.656 0.632 0.680 0.608 0.648 0.626 0.670 0.574

Serum cystatin C alone 0.665 0.641 0.689 0.056 0.654 0.632 0.676 0.101

C-statistics for mortality models

Visit 5: c-statistics for mortality C-statistic 95%CI, lower

95%CI, upper

p-value C-statistic 95%CI, lower

95%CI, upper

p-value

Base model 0.670 0.646 0.693 0.663 0.638 0.689

Creatinine Muscle Index 0.696 0.673 0.720 <0.001 0.698 0.674 0.723 <0.001

eGFRcys-eGFRcr 0.679 0.655 0.703 0.015 0.676 0.651 0.701 0.011

eGFRcys/eGFRcr 0.688 0.664 0.711 0.002 0.687 0.662 0.711 0.001

(6)

Scr/Scys 0.682 0.658 0.705 0.011 0.678 0.653 0.703 0.013

Serum creatinine alone 0.685 0.661 0.708 0.002 0.680 0.655 0.706 <0.001

Visit 2: c-statistics for mortality C-statistic 95%CI, lower

95%CI, upper

C-statistic 95%CI, lower

95%CI, upper

Base model 0.671 0.662 0.680 0.681 0.672 0.690

Creatinine Muscle index 0.687 0.678 0.696 <0.001 0.692 0.683 0.701 <0.001

eGFRcys-eGFRcr 0.683 0.674 0.692 <0.001 0.691 0.682 0.700 <0.001

eGFRcys/eGFRcr 0.683 0.673 0.692 <0.001 0.691 0.682 0.700 <0.001

Scr/Scys 0.682 0.673 0.691 <0.001 0.688 0.679 0.697 <0.001

Estimated creatinine excretion rate 0.676 0.666 0.685 <0.001 0.682 0.673 0.691 0.004

Serum creatinine alone 0.671 0.662 0.680 0.387 0.683 0.674 0.692 0.001

Base model includes age, height, weight, and education. P-value for difference from the base model. Other rows indicate models in which the variable is added to the base model.

(7)

Figure S1. Adjusted odds ratios of frail (vs robust) with continuous CMI in men and

women at visits 5 in ARIC. Reference point is cut off for upper tertile. Vertical lines are cutoffs

between tertiles. Adjusted for age, logACR, logCRP, total chol, HDL-C, current smoking,

education, center/race, prevalent CHD, hypertension, diabetes, BMI, eGFRB2M

(8)

References

1. Ix JH, Wassel CL, Stevens LA, Beck GJ, Froissart M, Navis G, et al. Equations to estimate creatinine excretion rate: the CKD epidemiology collaboration. Clin J Am Soc Nephrol. 2011;6(1):184-91.

2. Potok OA, Ix JH, Shlipak MG, Katz R, Hawfield AT, Rocco MV, et al. The Difference Between Cystatin C- and Creatinine-Based Estimated GFR and Associations With Frailty and Adverse Outcomes: A Cohort Analysis of the Systolic Blood Pressure Intervention Trial (SPRINT). Am J Kidney Dis. 2020;76(6):765- 74.

3. Akesson A, Lindstrom V, Nyman U, Jonsson M, Abrahamson M, Christensson A, et al. Shrunken pore syndrome and mortality: a cohort study of patients with measured GFR and known comorbidities. Scand J Clin Lab Invest. 2020;80(5):412-22.

4. Thongprayoon C, Cheungpasitporn W, Kashani K. Serum creatinine level, a surrogate of muscle mass, predicts mortality in critically ill patients. J Thorac Dis. 2016;8(5):E305-11.

Table of Contents

Supplement